Possible Cures for Type-1 in the News (March)

ViaCyte Starts A Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™
This clinical trial is studying people who were part of ViaCyte's clinical trial of VC-01™, an encapsulated beta cell cure.  Once the device is removed at the end of the study, the patients can enroll in this follow on study which tracks them for three additional years, looking for adverse effects.

ViaCyte is a commercial company testing an encapsulated beta cell cure.  You can read my previous blogging about them here: http://cureresearch4type1diabetes.blogspot.com/search/label/ViaCyte
They are in the middle of a large Phase-I study, which could finish as early as 2020.

Clinical record: https://clinicaltrials.gov/ct2/show/NCT02939118

Discussion

I'm hopeful that this means that one person has finished the ViaCyte protocol, which is motivating them to start this follow on.  The other option is that they are just planning ahead.  Since there is no control group, the interim data could be published, if ViaCyte wanted.

Two Phase-I Studies Start with Umbilical Cord Treg Cells 
These two studies have a lot in common, so I'm going to discuss them together: first, their similarities, then their differences. Here are the similarities:

• They are both run by the same researcher (Dr. Zhiguang Zhou) at the same hospital (Second Xiangya Hospital of Central South University).
• They recruit at the same place: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011
  Contact: Zhiguang Zhou, MD/PhD    86-731-85292154    zhouzg@hotmail.com
• They have already started recruiting 40 people, and expect to finish in 2019.
• These trials are open to people who have been diagnosed within 3 years and are between 6 and 60 years old.
• Each has a primary end point which is safety related, and secondary endpoints which are effectiveness related and include C-peptide, A1c, insulin usage, etc.
• Both studies will work with stem cells which have been harvested from umbilical blood, separated into components, and had the T-reg cells "grown out" for two weeks.  These enriched T-reg cells will be infused into patients.  T-reg cells are regulatory cells which are part of the immune system, and work by controlling other immune cells so that those other cells don't attack beta cells.

The first study is Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg on Autoimmune Diabetes: This study will have two groups, one will get the treatment, and one will be a control group and will not get the treatment.

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02932826

The second study is Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes: This study has four groups.  One will get the treatment and also Liraglutide, another just the treatment, a third just Liraglutide, and a fourth will be a control group.  Liraglutide (sold as Victoza) is similar to exenatide (Byetta), which is a common type-2 medication, but is also sometimes used on type-1.  Victoza is a weekly injection. 

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03011021

Discussion

The researchers are not clear on why they are using Liraglutide, but site its "various benefits for beta cells". They expect it will increase the effectiveness of the new T-regs, possibly by encouraging beta cell growth.

JDCA's Update on Dr. Faustman's Research

An update on Dr. Faustman's BCG research by the JDCA (Juvenile Diabetes Cure Alliance) is here:
http://eepurl.com/cHrGqX

My key takeaway points are:
* The Phase-II trial should finish in 2023.
* They have enrolled 125 out of the 150 they need.
* An 8 year follow up from their Phase-I trial should be published by the end of 2017.

(Remember, I am a fellow of the JDCA and we regularly discuss various research programs, including this one.)
Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Research In The News (July)

This is a combination of updates from the last month or two.

DILfrequency Completes Data Collection

In late may, the DILfrequency research team announced that they had finished collecting data, and were now starting to analyse that data.  Of course, that's great news, because it implies that results will be published in the next year or two.  (In my experience successful results are published within a year, unsuccessful results often take longer, if they are published at all.)

This study is testing Aldesleukin (also called Proleukin or IL-2) by giving it to adults within 5 years of diagnosis.  IL-2 is a component of the immune system, and they hope that more it will either improve or cure type-1 diabetes.  Are are looking for changes in the immune system which occurs quickly (ie. in a few weeks), or changes in insulin, A1c numbers, or C-peptide over a three month period.

I previously blogged on this study here:
http://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html

These researchers seem to be months ahead of schedule.  Previously, they expected to finish data collection by October 2016, but they have actually finished in May 2016, which is a testament to their ability to recruit people with type-1 diabetes.  Even better, they enrolled more people than expected: 36 expected vs. 41 actual, that's 14% bigger than planned for.  This group is very media-savvy, with lots of tweeting, facebook posting, a pinterest page, etc.  I suspect that this media focus helped them recruit, and I hope it represents the future of clinical trial recruiting techniques.

https://www.facebook.com/ClinicalTrialsType1Diabetes/?fref=nf
https://twitter.com/t1diabetestrial/status/735832240513515520/photo/1

New To Me: Cord Stem Cells In A Phase-II Clinical Trial

This trial started in 2009, but it registered with the US FDA's clinical trial registry in April 2016, and I did not know about it before then.  The basic plan is to give a total of 30 people a transplant of 3rd party umbilical cord stem cells (called allogeneic umbilical cord mesenchymal stem cells).  The people treated will be honeymooners (within 12 months of diagnosis), and must have had DKA when diagnosed.  There is no control group; everyone will get the treatment.  People will be followed for three years after transplant.  Primary outcome will be insulin usage, and secondary outcomes will be C-peptide, A1c, and autoantibody counts.  The researchers hope to finish collecting data in Dec 2019.

They are recruiting at one site:
Nanjing Drum Tower Hospital of Nanjing University Medical School. Nanjing, Jiangsu, China, 210008
Contact: Dalong Zhu, MD.PhD.    86-25-83106666 ext 61430    zhudalong@nju.edu.cn  
Contact: Jing Lu, PhD.    86-25-83106666 ext 61431    qiusnow16@hotmail.com  

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02763423

Discussion

This research is similar to Haller's work at the University of Florida, which completed a phase-I and started a phase-II clinical trial also in 2009.  I've blogged on that research here:
http://cureresearch4type1diabetes.blogspot.com/2009/05/haller-cord-blood-trial-results-from.html

Unfortunately, the phase-II study (which included a control group) completed in 2012 and was published in 2013, but was unsuccessful.  Exact quote was "Autologous UCB infusion followed by daily supplementation with vitamin D and DHA was safe but failed to preserve C-peptide.".

ATG Is Unsuccessful in a Phase-II Trial

58 people recently diagnosed with type-1 diabetes were given antithymocyte globulin (ATG) in the hopes that it would modulate the autoimmune attack on the pancreas's own beta cells.    The primary end point was C-peptide generation after 2 years (a measure of the body's ability to generate it's own insulin).  People who got the treatment did no better than people who did not.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/27053235
Trial Registration: https://clinicaltrials.gov/show/NCT00515099

Discussion

Although there was no improvement if the researchers looked at everyone in the study, if the researchers only looked at older patients (between 22 and 35 years old), then they did see a statistically significant improvement in C-peptide levels as compared to untreated patients of the same age.  The researchers were hopeful that future testing might show that ATG is helpful for older patients.

Diabetes Care Has A Section On Artificial Pancreas Papers

You can read 9 AP papers in one place:
http://care.diabetesjournals.org/content/39/7?etoc
Diabetes Care is published by the ADA.

Losing Autoantibodies: Does It Happen And What Does It Mean?

It is now well established that people test positive for autoantibodies before they are diagnosed with type-1 diabetes, and (statistically) more autoantibodies are detected over time as people move closer to diagnosis.  Also, there is a big difference between having one autoantibody and having more than one.  I'm sometimes asked: can someone lose an autoantibody that they previously had?  Put another way, are autoantibodies a one way progression to type-1 diabetes? Or can people move closer or farther away from diagnosis (at least as measured by number of autoantibodies).

The answer, according to this paper:
http://care.diabetesjournals.org/content/early/2016/06/13/dc16-0181?papetoc
is "its complicated".  Basically, some people do lose an autoantibody that they previously had and therefore, at least on paper, move away from type-1 diabetes.  However, in real life, most of the people who lose an autoantibody only had one to start with, and therefore were unlikely to ever be diagnosed with type-1 diabetes.  The people with more than one autoantibody (and who are likely to be diagnosed) rarely lose an autoantibody.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Eight New Stem Cell Clinical Trials For Type-1 Diabetes

I hate putting out half-digested information, but I'm convinced that I will never have time to fully digest all of these studies, so I'm putting out what I have, on the basis that something is better than nothing.

This is a list of eight studies, which are pretty similar.  They all involve using stem cells to treat or cure type-1 diabetes.  Some of these studies use adult stem cells, others embryonic, and others cord, although I think the most common is the patient's own bone marrow stem cells.

I consider stem cells to be one possible way to regenerate beta cells.  My opinion of beta cell regeneration in general, is that it is not going to cure type-1 diabetes by itself (because the autoimmune attack will kill the new beta cells same as the old ones) but that it might be an important part of the cure.  It's importance depends on how fast beta cells regrow after the autoimmune attack is stopped.  If they grow back quickly, then no form of beta regeneration will be needed, but if they grow back slowly or not at all, then some form of beta regeneration will be needed.  Stem cells are one form of beta cell regeneration, but there are others.  Exsulin and human growth hormone have been tested in people, and CureDM's drug in animals, and there are many more.

The good news here, is that there is a lot going on with stem cells, so if we do end up needing new beta cells to cure type-1 diabetes, here are 8 or more reasons why we are likely to have them.  And that is not even counting all the non-stem cell technologies out there.  But (in my opinion) the "gating factor" (what we in the software industry call the "critical path") to curing type-1 on this path is stopping the autoimmune response, not regenerating the beta cells.

As you read these, you will notice that some of them have end dates in the past, but are still active today.  Others have start dates in the past, but have not actually started recruiting patients.  These are signs that the researchers have not updated the clinical trial records, and need to.  This is quite common.  "Primary Completion" is when they finish collecting the data from the patients.

Uppsala University Hospital Stem Cell phase-I Trial
Treatment of Patients With Newly Onset of Type 1 Diabetes With Mesenchymal Stem Cells

Estimated Enrollment:	20
Study Start Date:	March 2010
Estimated Study Completion Date:	January 2012
Estimated Primary Completion Date:	January 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01068951


Armed Police General Hospital
Stem Cell Therapy for Type 1 Diabetes Mellitus
Cellonis Biotechnology Co. Ltd.

Estimated Enrollment:	24
Study Start Date:	August 2010
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	August 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01143168

Hospital Universitario Dr. Jose E. Gonzalez
Hematopoietic Stem Cell Transplantation in Type 1 Diabetes Mellitus

Estimated Enrollment:	15
Study Start Date:	May 2010
Estimated Study Completion Date:	March 2011
Estimated Primary Completion Date:	December 2010

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01143168

Shanghai Jiao Tong University School of Medicine 
Autologous Hematopoietic Stem Cell Transplantation for Early Onset Type 1 Diabetes

Estimated Enrollment:	30
Study Start Date:	February 2008
Estimated Study Completion Date:	February 2013
Estimated Primary Completion Date:	January 2013

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00807651

Veterens Memorial Medical Centre
Safety and Efficacy of Autologous Adipose-Derived Stem Cell Transplantation in Patients With Type 1 Diabetes
Adistem Ltd

Estimated Enrollment:	30
Study Start Date:	November 2007
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	November 2009

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00703599

Shandong University
Autologous Bone Marrow Mononuclear Cells Transplantation in Treating Diabetes Patients

Estimated Enrollment:	200
Study Start Date:	March 2006
Estimated Study Completion Date:	March 2014

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00465478

Technische Universität München
Cord Blood Infusion for Type 1 Diabetes Mellitus (T1DM)
23 patients, but no start or end dates provided
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00989547

University of Moron
Safety and Efficacy of Arterial Delivery of Autologous Bone Marrow Cells in the Treatment of Insulin-Dependent Diabetes
Stematix, Inc

Estimated Enrollment:	34
Study Start Date:	October 2009
Estimated Study Completion Date:	October 2014
Estimated Primary Completion Date:	October 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00971503


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Haller Cord Blood trial, results from Phase-I and Starting Phase-II

Haller at University of Florida is running a research program to transfuse into honeymoon diabetics their own (previously frozen) umbilical cord blood. Umbilical cord contains stem cells and also a lot of a specific type of T-cell (part of the immune system) called T-regulators. These cells help to regulate the immune system, and since type-1 diabetes is caused by a lack of immune regulation, this seems like a reasonable thing to try. Especially since more and more people are "banking" their children's umbilical cords at birth. The Phase-I study was focused on two possible paths to a cure: adult stem cells would migrate to the pancreas and help grow new beta cells, and/or T-regulators would help suppress the bad immune response. It appears that the adult stem cells path did not pan out, and the phase-II trial only discusses the T-reg mechanism, and not the adult stem cell mechanism.

So the basic status is that Haller has completed a phase-I trial, and gotten good results, and has started a phase-II trial.

The Phase-I Trial
It is supposed to involve 23 patients and run from April 2005 to July 2010, however the data I've seen covered 8 patients and was published in June 2007, so it is an interim result.

That said, the results were good: a few months after the transfusion, the treated kids had an average A1C 1 point lower than untreated (7 compared to 8), they used about 2/3 as much insulin per kg of body weight as the untreated patients, and they generated more C-peptide in response to food (meaning they generated more of their own insulin).

For the phase-I trial:
http://cordblood.cryosite.com/UserFiles/File/Cord%20Blood%20and%20Diabetes.pdf Nice summary
http://www.ncbi.nlm.nih.gov/pubmed/18358588 Phase-I Results Abstract
http://cordblood.net/cbrblog/haller-abstract.pdf Phase-I Results Whole Paper
http://clinicaltrials.gov/ct2/show/NCT00305344 Phase-I US Clinical Trial Record

The Phase-II Trial
It involves 15 patients (10 get treatment, 5 are the control group), and is scheduled to start March 2009 and finish collecting data by March 2012.

More details are described here:
http://clinicaltrials.gov/ct2/show/NCT00873925 Phase-II US Clinical Trial Record

My thoughts on this line of research are here; these are all personal opinions:
First, I think it is pretty limited in direct application, since it requires banked cord cells and is a honeymoon treatment. But I'm always hopeful that they might learn something that could be applied more broadly.
Second, I'm very interested in how long the effect lasts. Is it permanent, or does it go away over time?
Third, I think their "phase-II" experiment is tiny. Only 15 patients makes it smaller than some phase-I experiments that I've followed, and that's not a good sign.
Forth, this research "feels" to me like basic research where they're trying to better understand how adult stem cells and T-regulator cells might help type-1 diabetics, by experimenting on people. Rather than research on a short, straight line path to a cure.

Thanks to Ellen over at www.childrenwithdiabetes.com for pointing the phase-II trial out to me.

Joshua Levy